The overall goal of this PPG is to evaluate the hypothesis that calpain inhibition represents a viable[unreadable] therapeutic target for intervention following traumatic brain injury (TBI). TBI represents a leading cause of[unreadable] death and disability in adults and children, and improved treatment options are urgently needed. Calpains[unreadable] are excessively activated following TBI and are strongly implicated in the secondary neuronal degeneration.[unreadable] The resultant hypothesis is that calpain inhibition will protect against the pathological and functional[unreadable] consequences of TBI. Although straightforward, this hypothesis has proven to be surprisingly difficult to[unreadable] evaluate. A handful of studies in animal models of TBI have demonstrated improved neurological recovery[unreadable] and attenuated axonal injury with calpain inhibitor treatment. However, evidence that these benefits are[unreadable] directly related to calpain inhibition has been elusive. Moreover, there are numerous unanswered questions[unreadable] regarding the mechanisms by which calpains contribute to cell death and dysfunction. This PPG brings[unreadable] together investigators with strong expertise in calpain biochemistry and in animal models of TBI to evaluate[unreadable] three distinct mechanisms of calpain inhibition following TBI. Project 1 explores the role of the endogenous,[unreadable] specific, and potent calpain inhibitor, calpastatin, in modulating calpain function and improving outcome[unreadable] following TBI. Project 2 is translational and will investigate the ability of new small molecule calpain inhibitors[unreadable] to attenuate the pathological and functional consequences of TBI. Project 3 will examine the roles of[unreadable] individual calpain isoforms in neurodegeneration and TBI, focusing on the hypothesis that u-calpain is a[unreadable] pathologic isoform and is localized to mitochondria. In addition to the three projects, there will be three cores:[unreadable] A, Administrative and Biostatistical Core; B, Animal Core; and C, Proteomics and Biomarker Core. Together,[unreadable] these projects and cores will provide a clear indication as to whether calpain inhibition represents a viable[unreadable] therapeutic target for TBI, and whether the small molecule calpain inhibitors are suitable for subsequent[unreadable] preclinical and clinical investigation.